Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
Connections between epigenetic gene silencing and human disease
Section snippets
DNA methylation
Altered gene expression can play a causal role in human disease. In many cases, altered expression results from genetic lesions within the gene or regulatory sequences. However, in some cases genetic lesions are absent from the locus. In such instances, aberrant epigenetic modifications of the chromatin surrounding the gene are the cause of altered expression. There are two major epigenetic gene silencing mechanisms that account for a growing number of diseases: cytosine DNA methylation and
Histone methylation
Modifications such as phosphorylation, acetylation and methylation frequently occur on histones tails that extend from the nucleosome core [20]. These modifications serve to alter charge interactions of the histone tails with DNA, thereby influencing chromatin packaging. In addition, these modifications serve as binding sites for specific factors that “read” a proposed histone code [21]. In most cases, specific modifications correlate with biological functions such as chromatin condensation,
HP1 and disease
One function of K9H3 methylation is to serve as a binding site for HP1 (Fig. 1b). HP1 is conserved among species, with mice and humans each possessing three genes encoding HP1-like proteins [61]. In humans these are referred to as HP1Hsα, HP1Hsβ and HP1Hsγ. These proteins share significant amino acid sequence identity, yet have distinct chromosomal localization patterns [61], [62], [63]. HP1 proteins contain a chromo domain that binds methylated K9H3, and a chromo shadow domain that dimerizes
Connections among epigenetic gene silencing systems
Through the course of investigating the role of epigenetic modifications involved in disease, connections among DNA methylation, histone acetylation and histone methylation have become apparent (Fig. 1). Studies in model organisms have revealed a connection between DNA methylation and histone methylation. In Neurospora, a screen for mutants that lacked CpG DNA methylation identified a K9H3 histone methyltransferase [93]. In Arabidopsis, mutants lacking a histone H3 methyltransferase show
Dynamics of epigenetic modifications and therapy
The dynamic nature of epigenetic gene regulation is important to consider in the context of disease. Both the loss and gain of gene silencing at target genes can potentially be reversed through drug treatment [106]. Drugs that inhibit DNA methylation can reactivate silenced genes in cancer cells, possibly re-establishing cell cycle control [107]. Drugs that inhibit histone deacetylation block cell cycle progression and cause apoptosis by unknown mechanisms [107]. While HDAC inhibitors alter the
Acknowledgements
We apologize to the many investigators whose research could not be cited due to space limitations. We would like to thank Al Klingelhutz and members of the Wallrath Lab for comments on the manuscript, and Judith Kassis for discussions. Research is supported by an NIH grant (GM61513) to L.L.W., a grant from the Department of Defense Breast Cancer Research Foundation (DAMD17-02-1-0424) to L.L.W. and a Susan G. Komen Dissertation Research Award (DISS0403121) to T.J.M.
References (144)
- et al.
MeCP2 dysfunction in Rett syndrome and related disorders
Curr. Opin. Genet. Dev.
(2006) - et al.
The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression
Neuron
(2006) - et al.
The ups and downs of BDNF in Rett syndrome
Neuron
(2006) - et al.
Histones and histone modifications
Curr. Biol.
(2004) - et al.
Histone methyltransferase activity of a Drosophila Polycomb group repressor complex
Cell
(2002) - et al.
Division of labor in polycomb group repression
Trends Biochem. Sci.
(2004) - et al.
A bivalent chromatin structure marks key developmental genes in embryonic stem cells
Cell
(2006) - et al.
Searching chromatin for stem cell identity
Cell
(2006) - et al.
The EZH2 polycomb transcriptional repressor—a marker or mover of metastatic prostate cancer?
Cancer Cell
(2002) - et al.
Isolation and developmental expression analysis of Enx-1, a novel mouse Polycomb group gene
Mech. Dev.
(1996)